(1) Field of the Invention
The present invention relates to a composition and method for rapidly modifying the fatty acid composition of cell membranes in organs and tissues, in particular to increase the amount of omega-3 fatty acids in cell membranes of organs and tissues by parenterally administering to the human or animal body an appropriate supply of fatty acids in the form of an isotonic lipid emulsion comprising selected fatty acid triglycerides.
(2) Description of Related Art Including Information Disclosed Under 37 C.F.R. §§ 1.97 and 1.98.
Lipid emulsions have been known as an essential component of parenteral nutrition and are now being considered for other uses. Lipid emulsions for parenteral nutrition serve to supply the body with fats in an intravenously acceptable dosage form in cases where normal (oral) nutrition is impossible, comprised or medically contraindicated or when it is necessary to promptly modify the fatty acid pattern of the cells. The lipid emulsions currently available are prepared from vegetable oils (e.g., safflower or soybean oils). In some cases they also contain medium-chain triglycerides (MCT) and/or oils of marine origin (fish oils).
Long-chain triglycerides of vegetable or marine origin serve as an energy source and, when containing polyunsaturated fatty acids (“PUFA”), as suppliers of essential fatty acids. The classification of such polyunsaturated fatty acids into omega-6 (ω-6); in the art sometimes designated “n-6” PUFA) or omega-3 (ω-3, sometimes designated “n-3” PUFA) series is based on chemical structural features, more precisely, on the distance of the first unsaturated bond from the methyl end (omega end) of the fatty acid molecule. In the present description, for instance, “omega-3” has preferably been used.
The vegetable oils, e.g., of soybean and safflower, are characterized by a high content of polyunsaturated fatty acids of the omega-6 series (predominantly Linoleic acid, 18:2 omega-6) whereas their content of omega-3 fatty acids (almost exclusively in the form of α-linolenic acid, 18:3 omega-3 is low.
Fish oils (“FO”) obtained from cold-water fish are characterized by a high content of polyunsaturated fatty acids of the omega-3 series (predominantly cis-5,8,11,14,17-eicosapentaenoic acid, “EPA,” 20:5 omega-3, docosapentaenoic acid, “DPA,” 22:5 omega-3 and cis-4,7,10,13,16,19-docosahexaenoic acid, “DHA,” 22:6 omega-3) whereas their content of omega-6 fatty acids is low.
The medium-chain triglycerides (“MCT”) administered with the lipid emulsions serve mainly as a source of energy. Medium-chain triglycerides contain saturated fatty acids and hence contain neither the omega-6 nor omega-3 essential fatty acids. Because of their fast hydrolysis as well as other properties (enhancing particle binding to cells), MCT may have interesting influences on the metabolism of emulsion particles.
The human body is itself incapable of producing the vital, polyunsaturated long-chain fatty acids of the omega-6 or omega-3 series, i.e., they have to be administered orally, enterally or parenterally. The body is only able to synthesize longer-chain unsaturated fatty acids from shorter-chain ones. Both series compete for the same enzymatic system of elongation-desaturation. The formation of omega-6 fatty acids from precursors of the omega-3 series or vice versa is impossible, however.
In order that the exogenous free fatty acids are made available to the body, they must either be released hydrolytically from the infused triglycerides by means of the enzyme lipoprotein lipase (LPL) or be taken up together with emulsion particles or their remnants directly into the cells. This initial step of lipid hydrolysis has long been considered the rate-determining step of lipid metabolism. This limitation arises from the relatively limited activity of lipoprotein lipase in cleaving triglycerides. Thus, the maximum metabolizing rate for vegetable oil emulsions is about 3.8 g of lipid/kg body weight per day (Hallberg et al., Acta Physiol. Scand. (1965) Vol. 65, Suppl. 254, pp. 2-23).
During triglyceride infusion, it is desirable to achieve triglyceride serum concentrations which remain as low as possible, e.g., corresponding to a low load of the reticulo-endothelial system (RES) by exogenous lipids.
Typically, post-operative and post-traumatic conditions as well as severe septic episodes are characterized by a substantial stimulation of the immune system. The immune response involves the release of cytokines (e.g., tumor necrosis factor and interleukins) which, at high levels, may cause severe tissue damage. In addition, high cytokine concentrations also impair hydrolysis of circulating triglycerides by LPL.
In such clinical conditions, it is of particular importance to use exogenous triglycerides which are rapidly hydrolyzed and eliminated (to avoid excessive increases of plasma triglyceride concentration) and which supply fatty acids (e.g., omega-3 fatty acids) capable of reducing cytokine production as well as cytokine toxicity on tissues. This effect is obtained when fatty acids are cleaved from the triglyceride molecules and incorporated (in free form or as components of phospholipids) in cell membranes where they influence membrane structure (and function) and serve as secondary messengers and precursors of eicosanoids. Thus, it is desirable that this process take place as quickly as possible.
Triglycerides typical of fish oils are hydrolyzed much more slowly than triglycerides from vegetable oils (e.g., soybean oil) which are themselves hydrolyzed more slowly than medium-chain triglycerides. Addition of a fish oil emulsion to a long-chain triglyceride emulsion can even inhibit hydrolysis of long-chain triglycerides (e.g., from soybean oil) by LPL.
Description of Related Art Including Information Disclosed Under 37 CFR 1.97 and 1.98
European published patent application EP-A-0311091 discloses a lipid emulsion comprising medium chain triglycerides and a high amount of fish oil for parenteral nutrition.
International published patent application WO-A-90/08544 discloses fat emulsions comprising, as a source for omega-3 fatty acids, fish oil and 0 to 90%, based on the total lipid, of medium chain triglycerides and their intraperitoneal application for the treatment of septic affection of the abdominal cavity.
International published patent application WO-A-97/19683 discloses lipid emulsions comprising medium chain triglycerides, vegetable oils and fish oils for parenteral nutrition. WO-A-97/19683 also discloses the utility of said lipid emulsions for treating post-surgery, post-trauma, sepsis, inflammatory or wasting diseases, increased risk of vascular thrombosis and severe cardiac arrhythmia.
European published patent application EP-A-0687418 provides a lipid emulsion to limit the injury response in patients suffering from trauma, burns and/or sepsis, which lipid emulsion could be administered enterally or parenterally.
Simoens, C. et al. in Clinical Nutrition (1995), 14, 177-185 discloses the effects of the fatty acid composition in various tissues of four different vegetable-oil containing lipid emulsions. Sato, M. et al. in Journal of Parenteral and Enteral Nutrition (1994), 18, 112-118, discloses the hydrolysis of mixed lipid emulsions containing medium chain and long chain triglycerides with lipoprotein lipase in a plasma-like medium.
German published patent application DE-A-3721137 discloses the utility of a lipid emulsion comprising fish oil alone or fish oil in combination with vegetable oil and optionally medium chain triglycerides to parenteral nutrition and the reduction of the growth of tumors.
German published patent application DE-A-3409793 describes a lipid emulsion for infusion, which emulsion comprises fatty acids containing from 20 to 22 carbon atoms, esters thereof, or a mixture of 2 or more of such fatty acids or esters, as well as a vegetable oil, an emulsifier, and water. The fatty acids are fatty acids from esters of marine origin (fish oils), in particular, omega-3 fatty acids. Said vegetable oils are purified soybean and/or safflower oils.
The plasma clearance and tissue targeting of different intravenous lipid emulsions (fish oil; MCT/vegetable oil/fish oil; vegetable oil and mCT/vegetable oil) was compared in a mouse model by Treskova, E. et al. in Journal of Parenteral and Enteral Nutrition (2000), 23, 253-257. Billman, G. E. et al. in Circulation (1999), 99, 2452-2457 convincingly demonstrate that omega-3 fatty acids administered intravenously as their pure free fatty acid can prevent ischemia-induced ventricular arrhythmias in dogs.
From the above it can be derived that the major well-recognized roles of omega-3-polyunsaturated fatty acids are:
to decrease inflammatory and thrombotic reactions,                (i) to reduce cell reactivity to different stimuli (for example, to reduce cardiac arrhythmias, namely during myocardial infarct or ischemia, and to decrease cachexia in response to mediators such as TNFα, in conditions of cancer and inflammation),        (ii) to improve tissue micro-perfusion (e.g., during shock or after ischemia-reperfusion),        (iii) to improve intracellular antioxidant status (in spite of the well known sensitivity of PUFAs to peroxidation, which may be controlled by adequate amounts of liposoluble antioxidants), and        (iv) to limit intracellular fat accumulation.        
In addition, omega-3 PUFAs are essential for the maturation of the central nervous system (CNS) and the retina in the fetus and premature newborns. However, the rate of omega-3 fatty acid enrichment following oral supplementation substantially varies between different tissues and is particularly low in some regions of the brain and in the retina.
Although omega-3 fatty acids play essential functions at all these different levels, evolution of food intake in mankind is characterized by an important decrease in the consumption of omega-3 fatty acids and a rise of omega-6 fatty acid intake, especially in Western populations.
Still, benefits of omega-3 fatty acid supplementation have been confirmed in several clinical conditions with a strong correlation to omega-3 fatty acid concentration into cell membrane phospholipids.